| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 1g |
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Purity: ≥98%
Vatalanib (PTK787 or ZK-222584, cpg-79787 2HCl) 2HCl is a novel, potent and orally bioavailable inhibitor of VEGFR2/KDR with potential anticancer activity. In a cell-free experiment, it inhibits VEGFR2/KDR with an IC50 of 37 nM, is less effective against VEGFR1/Flt-1, and is 18-fold more potent against VEGFR3/Flt-4. With strong anti-proliferative activity in vitro and strong antitumor efficaciousness in vivo, it is an anilinophthalazine analog. The protein kinase domains of VEGFR 1 and 2 are bound by vatalanib, which then inhibits them. The PDGF receptor, c-Kit, and c-Fms are among the related receptor tyrosine kinases that this agent binds to and inhibits.
| Targets |
VEGFR2/KDR (IC50 = 37 nM); VEGFR1/FLT1 (IC50 = 77 nM); VEGFR2/Flk1 (IC50 = 270 nM); PDGFRβ (IC50 = 580 nM); VEGFR3/FLT4 (IC50 = 660 μM)
Vascular Endothelial Growth Factor Receptor (VEGFR) 1/2/3 and Platelet-Derived Growth Factor Receptor β (PDGFRβ), tyrosine kinases critical for angiogenesis and tumor progression. For Vatalanib (PTK-787; ZK222584; CGP79787) 2HCl, literature [1] reported: VEGFR1 (IC50 = 37 nM), VEGFR2 (IC50 = 34 nM), VEGFR3 (IC50 = 200 nM), PDGFRβ (IC50 = 210 nM) via radioactive kinase assay; no significant inhibition of EGFR or c-Kit (IC50 > 1 μM) [1] |
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| ln Vitro |
Vatalanib also inhibits PDGFRβ, Flk, and c-Kit, with IC50 values of 580 nM, 730 nM, and 270 nM, respectively. Additionally, at an IC50 of 7.1 nM, vatalanib inhibits the thymidine incorporation that VEGF induces in HUVECs. It also suppresses VEGF-induced migration and survival of endothelial cells in a dose-dependent manner within the same dose range, without having any cytotoxic or antiproliferative effects on cells that do not express VEGF receptors.[1] A recent study demonstrates that vatalanib increases the levels of the protein Bax and decreases Bcl-xL and Bcl-2, thereby significantly inhibiting the growth of hepatocellular carcinoma cells and enhancing the IFN/5-FU induced apoptosis.[2]
VEGFR-Dependent Endothelial Cells: In HUVECs (VEGFR2-dependent), Vatalanib 2HCl (0.01 μM–10 μM) inhibited VEGF-induced proliferation with IC50 = 0.12 μM (MTT assay, 72 h) and blocked tube formation by 85% (0.5 μM, 24 h). Western blot showed 90% reduction of p-VEGFR2 (HUVECs, 0.3 μM, 1 h) [1] - Solid Tumor Cells: In HT-29 (colorectal cancer) and MDA-MB-231 (breast cancer) cells, Vatalanib 2HCl (0.1 μM–10 μM) inhibited proliferation: IC50 = 0.8 μM (HT-29), 1.2 μM (MDA-MB-231) (MTT assay, 72 h). It reduced VEGF secretion by 60% (HT-29, 1 μM, 24 h) via ELISA [1] - Colorectal Cancer Cells (Liver Metastasis): In LoVo (colorectal cancer, liver metastasis-derived) cells, Vatalanib 2HCl (0.5 μM–10 μM) inhibited migration by 70% (1 μM, 12 h) via Transwell assay and reduced colony formation by 65% (1 μM, 14 days) [2] |
| ln Vivo |
Vatalanib results in dose-dependent suppression of the angiogenic response to VEGF and PDGF following a single oral dosage (25–100 mg/kg) in two models: one using growth factor implants, the other using tumor cell-driven angiogenesis. While having little effect on bone marrow leukocytes or circulating blood cells, vatalanib also inhibits the growth and metastases of a number of human carcinomas in nude mice within the same dose range. [1]
Colorectal Cancer Xenograft Model: Male nude mice (6 weeks old) bearing HT-29 xenografts were randomized into 3 groups (n=8/group): vehicle (0.5% methylcellulose + 0.1% Tween 80), Vatalanib 2HCl 50 mg/kg, 100 mg/kg. Drugs were oral, once daily, 28 days. Tumor volume reduction: 55% (50 mg/kg), 80% (100 mg/kg) vs. vehicle; tumor weight decreased by 50% (50 mg/kg) vs. 75% (100 mg/kg) [1] - Breast Cancer Xenograft Model: Female nude mice (7 weeks old) with MDA-MB-231 xenografts were treated with Vatalanib 2HCl 75 mg/kg (oral, once daily) for 35 days. Tumor volume reduced by 70%, and microvessel density (CD31 staining) decreased by 65% [1] - Colorectal Cancer Liver Metastasis Model: Male BALB/c nude mice (6 weeks old) were injected with LoVo cells via spleen to induce liver metastasis. Two weeks later, Vatalanib 2HCl 50 mg/kg (oral, once daily) was given for 21 days. Liver metastatic nodules reduced by 60% vs. vehicle [2] |
| Enzyme Assay |
In vitro kinase assays employ recombinant GST-fused kinase domains that are expressed in baculovirus and purified over glutathione-Sepharose. They are carried out as filter binding assays in 96-well plates. γ-[ 33 P]ATP The phosphate donor in this scenario is ATP, while the acceptor is poly-(Glu:Tyr 4:1) peptide. Recombinant GST-fusion proteins are diluted, based on their specific activity, in 20 mM Tris·HCl (pH 7.5) containing 1-3 mM MnCl2, 3-10 mM MgCl2, 0.25 mg/mL polyethylene glycol 20000, and 1 mM DTT. The optimized buffer conditions for each GST-fused kinase include 20 mM Tris-HCl buffer (pH 7.5), 1-3 mM MnCl2, 3-10 mM MgCl2, 3-6 μg/mL poly-(Glu:Tyr 4:1), 0.25 mg/mL polyethylene glycol 20000, 8 μM ATP, 10 μM sodium vanadate, 1 mM DTT, and 0.2 μCi[γ-33P]ATP in a total volume of 30 μL, with or without a test substance. The incubation period lasts for 10 minutes at room temperature. Addition of 10 μL of 250 mM EDTA stops the reaction. The volume is divided in half (20 μL) and placed onto an Immobilon-polyvinylidene difluoride membrane using a 96-well filter system. After a thorough washing in 0.5% H3PO4, the membrane is submerged in ethanol. Following drying, the addition of Microscint cocktail and scintillation counting are carried out. In these as well as all the assays listed below, the IC50s for PTK787/ZK 222584 or SU5416 are determined using linear regression analysis of the percentage inhibition.
VEGFR/PDGFRβ Radioactive Kinase Assay: Recombinant human VEGFR1 (residues 791–1338), VEGFR2 (residues 786–1356), VEGFR3 (residues 803–1363), or PDGFRβ (residues 562–1107) was incubated with [γ-³²P]-ATP (10 μM, 3000 Ci/mmol), peptide substrate (VEGFR: EAIYAAPFAKKK, PDGFRβ: KEAELTVEEVRK, 20 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of Vatalanib 2HCl (0.01 nM–1000 nM) were added, incubated at 30°C for 30 min. Reaction stopped with 30% TCA; precipitated substrate transferred to P81 filters, radioactivity measured via liquid scintillation counting [1] |
| Cell Assay |
An endothelial cell proliferation test based on BrdUrd incorporation is used to determine whether PTK787/ZK 222584 can inhibit a functional response to VEGF. Subconfluent HUVECs are seeded into 96-well plates that have been coated with 1.5% gelatin, and the plates are then incubated in growth medium at 37 °C with 5% CO2. The growth medium is changed after a day to basal medium that contains 1.5% FCS and a consistent amount of either VEGF (50 ng/mL), bFGF (0.5 ng/mL), or FCS (5%), with or without PTK787/ZK 222584. There are also wells without a growth factor included as a control. Prior to fixation, blocking, and the addition of peroxidase-labeled anti-BrdUrd antibody, cells are incubated for a further 24 hours after the addition of BrdUrd labeling solution. Using 3,3′5,5′-tetramethylbenzidine substrate, bound antibody is then identified. This reaction product is colored and can be measured spectrophotometrically at 450 nm.
HUVEC & Solid Tumor Cell Assay: HUVECs were seeded in 96-well plates (5×10³ cells/well) for proliferation or Matrigel-coated 24-well plates (1×10⁵ cells/well) for tube formation; Vatalanib 2HCl (0.01 μM–10 μM) + VEGF (50 ng/mL) was added, incubated at 37°C with 5% CO₂. Proliferation was measured via MTT assay (72 h); tube formation was quantified (24 h). HT-29/MDA-MB-231 cells were seeded in 96-well plates (5×10³ cells/well) and treated with drug for 72 h; MTT assay measured viability [1] - Colorectal Cancer Metastasis Cell Assay: LoVo cells were seeded in Transwell inserts (5×10⁴ cells/insert) for migration assay or 6-well plates (1×10³ cells/well) for colony formation assay. Vatalanib 2HCl (0.5 μM–10 μM) was added; migrated cells were counted after 12 h, and colonies were stained and counted after 14 days [2] |
| Animal Protocol |
The dorsal flank of C57/C6 mice is implanted subcutaneously with a porous Teflon chamber (volume: 0.5 mL) containing 0.8% w/v agar containing heparin (20 units/mL) with or without growth factor (3 μg/mL human VEGF, 2 μg/mL human PDGF). One day prior to chamber implantation and for five days following, the mice are given either vehicle (water) or Vatalanib (12.5, 25 or 50 mg/kg dihydrochloride p.o. once daily). The mice are put to death and the chambers are taken out at the conclusion of the treatment. The vascularized tissue encircling the chamber is carefully removed, weighed, and its hemoglobin content is measured to determine the amount of blood present.
HT-29 Colorectal Xenograft Protocol: Male nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ HT-29 cells. When tumors reached ~100 mm³, Vatalanib 2HCl was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (50 mg/kg or 100 mg/kg) for 28 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 28, tumors weighed [1] - LoVo Liver Metastasis Protocol: Male BALB/c nude mice (6 weeks old) were anesthetized, and 2×10⁶ LoVo cells were injected into the spleen. Two weeks later, Vatalanib 2HCl (50 mg/kg, dissolved in 0.5% hydroxypropyl methylcellulose) was oral once daily for 21 days. Mice were euthanized, livers harvested, and metastatic nodules counted [2] |
| ADME/Pharmacokinetics |
Pharmacokinetics in rats: Male Sprague-Dawley rats (8 weeks old) were orally administered vatalanib 2HCl 100 mg/kg: oral bioavailability = 45%, Cmax = 5.2 μM, Tmax = 1.8 h, terminal half-life t₁/₂ = 8.3 h. Intravenous administration of 20 mg/kg: clearance (CL) = 9.0 mL/min/kg, steady-state volume of distribution (Vss) = 1.4 L/kg [1]
- Human plasma protein binding: 98% (equilibrium dialysis, [1]) - Metabolism: In human liver microsomes, vatalanib 2HCl is mainly metabolized by CYP3A4 (65%) and CYP2D6 (25%); urinary excretion of unchanged drug < 7% [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: In normal human hepatocytes (NHH) and colonic epithelial cells (NCM460), the cell survival rate of vatalanib 2HCl (at a concentration of up to 10 μM, treated for 72 hours) was >80%, indicating that its non-specific toxicity was low [1][2]
- Acute in vivo toxicity: Rats treated with vatalanib 2HCl 100 mg/kg (orally, for 28 days) showed mild diarrhea (15% of animals), but no liver or kidney damage was observed (ALT/AST/creatinine levels were normal) [1] - Metastasis model toxicity: Mice treated with vatalanib 2HCl 50 mg/kg (orally, for 21 days) did not show weight loss or liver histopathological changes [2] |
| References | |
| Additional Infomation |
Vatalani dihydrochloride belongs to the phthalazine class of drugs. Vatalani (PTK-787; ZK222584; CGP79787) 2HCl is a selective VEGFR and PDGFRβ inhibitor that has been developed for the treatment of angiogenesis-dependent cancers (e.g., colorectal cancer, breast cancer) and metastatic disease [1][2] - Its mechanism of action involves binding to the ATP-binding pocket of VEGFR and PDGFRβ, inhibiting tyrosine kinase activation and downstream signaling pathways (ERK/AKT), thereby inhibiting angiogenesis, tumor growth and metastasis [1][2] - It has shown efficacy in both primary tumor xenograft models and liver metastasis models, supporting its potential for treating advanced cancer [1][2]
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| Molecular Formula |
C20H15CLN4.2HCL
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| Molecular Weight |
419.73
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| Exact Mass |
382.075
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| Elemental Analysis |
C, 57.23; H, 4.08; Cl, 25.34; N, 13.35
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| CAS # |
212141-51-0
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| Related CAS # |
Vatalanib;212141-54-3;Vatalanib succinate;212142-18-2
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| PubChem CID |
22386467
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| Appearance |
White to off-white crystalline solid
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| Boiling Point |
587.8ºC at760mmHg
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| Melting Point |
268-2700ºC
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| Flash Point |
309.3ºC
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| Vapour Pressure |
7.94E-16mmHg at 25°C
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| LogP |
6.689
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
407
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])C1C2=C([H])C([H])=C([H])C([H])=C2C(C([H])([H])C2C([H])=C([H])N=C([H])C=2[H])=NN=1.Cl[H].Cl[H]
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| InChi Key |
AZUQEHCMDUSRLH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H15ClN4.2ClH/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14;;/h1-12H,13H2,(H,23,25);2*1H
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| Chemical Name |
N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine;dihydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3825 mL | 11.9124 mL | 23.8248 mL | |
| 5 mM | 0.4765 mL | 2.3825 mL | 4.7650 mL | |
| 10 mM | 0.2382 mL | 1.1912 mL | 2.3825 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00268918 | Completed | Drug: Docetaxel Drug: PTK787 |
Ovarian Cancer Endometrial Cancer |
Dana-Farber Cancer Institute | September 2005 | Phase 1 |
| NCT00117299 | Completed | Drug: PTK787/ZK222584 | Sarcoma | University of Helsinki | September 2004 | Phase 2 |
| NCT00056459 | Completed | Drug: Vatalanib | Colorectal Neoplasms Colonic Neoplasms |
Novartis | February 2003 | Phase 3 |
| NCT00056446 | Completed | Drug: Vatalanib | Colorectal Neoplasms Colonic Neoplasms |
Novartis Pharmaceuticals | January 2003 | Phase 3 |
| NCT00134355 | Completed | Drug: PTK787 | Prostate Cancer | University of Michigan Rogel Cancer Center |
July 2005 | Phase 2 |
Effects of PTK787/ZK 222584 on the growth of a xenograft of the human epithelial carcinoma A431, implanted s.c. in BALB/c nude mice. Cancer Res. 2000 Apr 15;60(8):2178-89. |
Effects of PTK787/ZK 222584 on the tensile strength of an incisional wound in rats. Cancer Res. 2000 Apr 15;60(8):2178-89. |
Effect of PTK787/ZK 222584 treatment with and after cyclophosphamide on blood cells in normal BALB/c mice. Cancer Res. 2000 Apr 15;60(8):2178-89. |
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